Coronavirus disease (COVID-19) in patients with type 2 diabetes mellitus: clinical and laboratory peculiarities

This study aims to study the clinical-laboratory peculiarities of the coronavirus disease (COVID-19) course in patients with type 2 diabetes mellitus (DM). There were examined 60 patients with the coronavirus disease COVID-19. Patients were divided into two groups: group I - 30 patients with the coronavirus disease (COVID-19) with concomitant type 2 diabetes mellitus;group II - 30 patients with coronavirus disease (COVID-19) without diabetes mellitus;control group - 20 people. There were studied peculiarities of clinical-laboratory changes in patients with coronavirus disease with type 2 diabetes mellitus. General clinical laboratory tests, determination of biochemical parameters, coagulogram, ferritin, CRP, procalcitonin, D-dimer and endothelin-1 were performed. Blood saturation was measured. Out of the instrumental methods, an ultrasound examination of the lungs and RTG of thoracic organs was performed. Patients were admitted on the 5.46+/-0.87 day of the disease. The length of the hospital stay for patients of group I was 19.9+/-1.66 bed days and 14.7+/-0.91 bed days for the patients of group II. A severe course of the disease was observed in 83.3% of patients of group I and 33.3% of group II;a moderate severity course was observed in 16.7% of patients with concomitant DM and 66.7% of patients without concomitant DM. Respiratory failure (RF) of 1 degree was observed in 30% of patients of group 1, RF of the 2 degree - in 16.7% of patients, and RF of the 3 degree - in 10% of patients. In patients without DM, RF of 1 degree - was in 30% of patients, and RF of the 2 degree - was in 13.3% of patients. The laboratory diagnostic methods determined that the levels of leukocytes, D-dimer, endothelin-1, IL-6, procalcitonin, and ferritin were higher in patients with concomitant type 2 DM. In patients with type 2 DM, the course of the coronavirus disease is more severe and longer, with the development of pneumonia and respiratory failure. It is accompanied by leukocytosis, lymphopenia, increased ESR, prothrombin index, IL-6, CRP level, procalcitonin and endothelin-1. Copyright © 2023 The Authors.

Blood Pressure, Proteases and Inhibitors

Blood pressure is controlled through a complex network of interacting peptide systems, principally involving the angiotensin, natriuretic peptide, endothelin and apelin families. The most complex and thoroughly investigated is the renin-angiotensin system (RAS) in which selective and potent inhibitors of the key biosynthetic proteolytic enzymes, renin and angiotensin-converting enzyme (ACE), have proved to be valuable drugs for the effective treatment of hypertension and heart failure, as well as other cardiovascular and renal disorders. Some of the other proteases in these pathways, e.g.neprilysin and ACE2, are also being explored as potential drug targets. © 2023 Elsevier Inc. All rights reserved.

Which biomarker(s) to predict worsening of SARS-CoV2 infection? An ancillary study from the COVIDeF cohort

Introduction: COVID-19 has been responsible for millions of deaths and intensive care unit (ICU) admissions all over the world. Identifying the patients at risk of developing a severe form is crucial for an optimized orientation and allocation of resources. The main objective of our study was to identify among a selection of biomarkers, those predictive of short term worsening in COVID-19. Method(s): This is an ancillary study using clinical data and collected biobanking from the multicentric cohort study COVIDeF, which included prospectively from March 31th 2020 to March 30th 2021, patients admitted with a suspected Sars-CoV2 infection in the Assistance- Publique-Hopitaux de Paris network, France. Patients with confirmed COVID-19 were divided in 2 groups: a severe (ICU admission or invasive or non-invasive ventilation or ARDS or death) and a control group (no worsening). The routine blood tests and following biomarkers: troponin, C Reactive Protein (CRP), procalcitonin, Mild- Regional pro-Adrenomedulin (MR-proADM), pro-endothelin, SuPAR, NT-proBNP, calprotectin, PF4, D-dimers, were measured in plasma or serum and compared between both groups using a conditional logistic regression. Result(s): Among the 1040 first patients included in the COVIDEF cohort, we selected 512 patients having a blood sample drawn at admission before worsening, of which 60 secondarily worsened (severe group). The mean age was 59.5 (+/- 19.5) years and 50.2% were females. Among the biomarkers tested, three were independently associated with worsening: CRP (mg/l) OR 1.01 [IC 1.01-1.02], procalcitonin (ng/ml) OR 0.4428 [0.21-0.95] and MR-proADM (pg/ml) OR 3.012 [1.06-8.53]. Conclusion(s): Among a selection of biomarkers of interest, MRproADM appears to best identify at admission COVID-19 patients at risk of worsening. Future interventional studies should test the efficacy and security of this biomarker to rule-in and rule-out severe outcome and the usefulness for allocating resources.

Investigating monotherapy and combination therapy trends in newly diagnosed patients with pulmonary arterial hypertension among EU3 & UK physicians over the COVID-19 pandemic

Background: Pulmonary Arterial Hypertension (PAH) is a form of pulmonary hypertension, where the narrowing of arteries in the lungs restricts blood flow and so increases pressure in the vessels. Studies have demonstrated that initial combination therapies are optimal for PAH management. However, prescription of monotherapy treatment is still prevalent as a first line therapy. Purpose(s): The purpose of this research was to investigate prescribing trends of physicians for first line patients with PAH in the UK, Germany, Italy and Spain. We investigated the proportions of newly diagnosed patients and the prescription trends for monotherapy and combination therapy prior to and during the COVID-19 pandemic. Method(s): A multi-country, multi-centre online medical chart review study of patients with PAH was conducted between April - June of 2019, 2020 and 2021 respectively. Recruited from a large access panel, 178 treating cardiologists, pulmonologists & rheumatologists in the UK (n=16), Germany (n=55), Italy (n=55) and Spain (n=52) were screened for duration of practice in their speciality and caseload (>=5 PAH patients in the last 3 months), and provided data on 694 PAH patients (UK = 71, Germany = 206, Italy = 208, Spain = 209). Reported patient data pertained to medical chart information reflecting the prior year, i.e., Q2 2021 data reflected the 2020 period (advent of the COVID-19 pandemic). Result(s): In this dataset, there has been a consistent decrease in the proportion of newly diagnosed (i.e. diagnosed within 12 months of being reported) patients reported from 2019 to 2020 and 2021. In 2019, 49% of the reported patients were diagnosed within the last 12 months. However, the newly diagnosed patient population dropped to 37% in 2020 and continued to drop to 27% in 2021. Despite this, there has been an increase in reported first line patients within the newly diagnosed segment from 74% in 2019, to 75% in 2020, then at 87% in 2021. This increase can be seen to coincide with the ongoing COVID-19 pandemic. In 2019, 58% of reported newly diagnosed patients were recorded as receiving monotherapy. This did drop to 33% in 2020;however, in 2021 monotherapy uptake increased to 47%. Of note, the usage of the endothelin receptor antagonist (ERA) drug class increased from 67% in 2019 to 83% in 2020 but dropped to 69% in 2021. Conclusion(s): This data set suggests a decreasing trend in newly diagnosed patients and a gradual shift in treatment type to first line monotherapy prescription, which coincided with the height of the COVID-19 pandemic. More newly diagnosed patients (those diagnosed within 12 months of being reported) are receiving monotherapy treatment at the expense of combination therapy, and this has also coincided with the pandemic. Further investigation using comparator cohort is warranted to assess whether the challenges physicians faced during the pandemic has had a causal effect on the prescribing habits for PAH therapies.

Prolonged stay and endothelial dysfunction in hospitalized patients with covid-19

Introduction: COVID-19 is not only a respiratory disease, produces a severe systemic and multi-organ response. This illness generates vascular disorders, leading the patient to endothelial dysfunction. It acutely and chronically affects the patient's evolution, prolonging the patient's stay and worsening life prognosis. Objective(s): To evaluate differences in endothelial dysfunction present in patients hospitalized for COVID-19 who had a hospital stay longer than 18 days compared to those who did not. Method(s): A prospective cohort study was conducted. Hospitalized patients with confirmed SARS-COV 2 andolder than 18 years were included. Subjects in whom endothelial function markers could not be processed wereexcluded. Endothelial dysfunction was evaluated using E-selectin, endothelin-1, glutathione-s-transferase, arginase, and MDAM. A prolonged hospital stay was established >=18 days. Result(s): A total of 165 patients were evaluated, the average age of the population was 57.18 +/- 13.37 years, 73.33% were men. Subjects with prolonged hospital stay were older (59.38 +/- 12.08 vs 51.15 +/- 14.96, p=0.004), a higher number of patients required intubation (87.60 % vs 75, p=0.049) and e-selectin (1 [0.79 - 1.32] vs 0.88 [0.68 -1.14], p=0.0323) compared to subjects without prolonged hospital stay. Conclusion(s): Hospitalized patients over 18 days showed elevated levels of E-selectin reflecting endothelial damage, affecting vascular homeostasis, added to this, a significant number of them were intubated, increasing the risk of mortality, as well as future cardiovascular complications.

The Seventeenth International Conference on Endothelin (ET-17).

The Seventeenth International Conference on Endothelin (ET-17) was held during 4-7 October 2021 and because of the SARS-CoV-2 pandemic it was held virtually. Sponsored by the American Physiological Society, ET-17 was held over 4 half-days, with exciting studies related to all organ systems presented. Since the Lancet article reporting the successful SONAR clinical trial with endothelin receptor A blockade in diabetic nephropathy, there has been renewed interest in the use of endothelin receptor antagonists in the treatment of a variety of diseases. From the rigorous preclinical studies to the latest clinical trials, ET-17 was full of exciting science, some of which is reported in this special issue. We welcomed new labs to the meeting and everyone left with the impression that ET-related research is a vibrant field with very significant discoveries being made.

COVID-19 and Pulmonary Embolism

Purpose. To establish the features of laboratory indicators of inflammation and endothelial dysfunction in persons with new SARS-CoV-2 coronavirus infection and pulmonary artery thromboembolism verified by computed tomographic angiography. Materials and methods. The study enrolled 116 patients with the confirmed coronavirus infection SARS-CoV-2 who were treated in the health care institution "4th City Clinical Hospital named after N.E. Savchenko" of Minsk in whom computed tomographic angiography (CTA) was performed to verify the diagnosis of pulmonary embolism (PE). The median age of the subjects was 62.0 (52.0–70.0) years, the proportion of males was 45.7% (53), females – 54.3% (63). The study group consisted of patients with SARS-COV-2 and confirmed diagnosis of PE (n=37), comparison group included patients with SARS-COV-2 whose diagnosis of PE was excluded on CTA (n=79). The formed groups were comparable by gender, age, presence of diabetes mellitus, bad habits, degree of arterial hypertension, and severity of course of COVID-19. The serum levels of tumor necrosis factor alpha (TNF-a), interleukin-6 (IL-6), interleukin-1 beta (IL-1β), big endothelin-1 (Big ET-1), homocysteine were determined on the day when CTA was performed by enzyme immunoassay (EIA). A level of D-dimer on the day when CTA was performed was additionally analyzed. Results. In individuals with coronavirus infection and PE group mean values of IL-6, D-dimer, big ET-1, and homocysteine were significantly higher compared with the group without PE: 41.65 (21.84–136.36) versus 25.79 (15.93–36.17) pg/mL (U=135, p<0.05);2058.5 (826.0–4026.0) versus 982.5 (656.5–1936.0) ng/mL (U=141.5, p<0.05);0.34 (0.26– 0.51) versus 0.29 (0.07–0.38) pg/ml (U=137, p<0.05);19.55 (13.81–23.84) versus 16.01 (11.07–19.13) pg/ml (U=139, p<0.05) respectively. There were no significant differences between group mean values of TNF-a, interleukin-1β in the study and comparison groups. In the group of patients with PE and COVID-19 values of IL-6 and big ET-1 (ρ=0.66;p<0.05);TNF-a (ρ=0.62;p<0.05) were moderately positively correlated, values of IL-6 and D-dimer (ρ=0.78;p<0.05);interleukin-1β (ρ=0.80;p<0.05) were highly positively correlated. Conclusion. The obtained data demonstrates that in patients with COVID-19 and PE the course of the disease is accompanied by a more pronounced increase in serum levels of markers of inflammation (IL-6) and endothelial dysfunction (large endothelin-1, homocysteine). The correlation between the levels of IL-6 and big ET-1, D-dimer indicates the association of the activity of systemic inflammation with the level of endothelial dysfunction markers. © 2022, Professionalnye Izdaniya. All rights reserved.

Role of endothelial dysfunction in the severity of COVID­19 infection (Review).

COVID­19 patients with severe infection have been observed to have elevated auto­antibodies (AAs) against angiotensin II receptor type 1 (AT1R) and endothelin (ET) 1 receptor type A (ETAR), compared with healthy controls and patients with favorable (mild) infection. AT1R and ETAR are G protein­coupled receptors, located on vascular smooth muscle cells, fibroblasts, immune and endothelial cells, and are activated by angiotensin II (Ang II) and ET1 respectively. AAs that are specific for these receptors have a functional role similar to the natural ligands, but with a more prolonged vasoconstrictive effect. They also induce the production of fibroblast collagen, the release of reactive oxygen species and the secretion of proinflammatory cytokines (including IL­6, IL­8 and TNF­α) by immune cells. Despite the presence of AAs in severe COVID­19 infected patients, their contribution and implication in the severity of the disease is still not well understood and further studies are warranted. The present review described the major vascular homeostasis systems [ET and renin­angiotensin­aldosterone system (RAAS)], the vital regulative role of nitric oxide, the AAs, and finally the administration of angiotensin II receptor blockers (ARBs), so as to provide more insight into the interplay that exists among these components and their contribution to the severity, prognosis and possible treatment of COVID­19.

Interactive Web-Based Lung Cell Atlases Lower Barriers to Transcriptomic Data Sharing, Mining and Dissemination

Rationale: Recent advancements in sequencing technologies have led to a substantial increase in the scale and resolution of transcriptomic data. Despite this progress, accessibility to this data, particularly among those who are coming from non-computational backgrounds is limited. To facilitate improved access and exploration of our single-cell RNA sequencing data, we generated several data sharing, mining and dissemination portals to accompany our idiopathic pulmonary fibrosis (IPF), chronic obstructive pulmonary disease (COPD), and lung endothelial cells (Lung EC) cell atlases. Descriptions and links of each website can be found here: https://medicine.yale.edu/lab/kaminski/research/atlas/. Methods: Each interactive data mining website is coded in the R language using the Shiny package and is hosted by Shinyapps.io. Percell expression data for each website is stored on a MySQL database hosted by Amazon Web Services (AWS). Time-associated website engagement statistics and gene query information is collected for each website using a combination of Google Analytics and a gene search table stored on our MySQL database. User exploration of available data is facilitated through several easy-touse visualization tools available on each website. Results: Website usage statistics since the publication of each website shows that 9,772 unique users from 56 countries and five continents have accessed at least one of the three websites. At the time of writing, 300,748 total queries have been made for 15,627 unique genes across the websites. The top five searched genes for the IPF Cell Atlas are CD14, ACE2, ACTA2, IL11 and MUC5B while for the COPD Cell Atlas they are FAM13A, MIRLET7BHG, HHIP, ISM1 and DDT. Finally, the top searched genes for the Lung Endothelial Cell Atlas are BMPR2, PECAM1, EDNRB, APLNR and PROX1. Of note, interaction with the IPF Cell Atlas increased dramatically at the start of the COVID-19 pandemic, with queries for the ACE2 gene, the putative binding receptor for the SARS-CoV-2 virus, increasing substantially at the pandemic's onset in the United States. Conclusions: Usage statistics, gene query information and feedback from users, both within academia and industry, have shown broad engagement with our websites by individuals across computational and non-computational backgrounds. We envision widespread adoption of web-based portals similar to ours will facilitate novel discoveries within these complex datasets and new scientific collaborations.

The Dual-Endothelin1/VEGFsp Receptor (DEspR) - Potential Role in Chronic Respiratory Diseases

Background The translatability of the dual-endothelin1/VEGFsp receptor (DEspR) in human was first described in 2016 and its functionality is largely unknown since DEspR is not expressed in healthy human tissues except for kidney tissue and certain tumors. Recently, DEspR expression was reported on human neutrophil subsets of acute respiratory distress syndrome (ARDS) and COVID19-ADRS patients. DEspR+ neutrophil levels correlated with disease severity and mortality which may root in their delayed apoptosis and facilitated formation of neutrophil extracellular traps. Neutrophils play a major role in inflammation of chronic respiratory diseases and altered levels of DEspR ligands ET-1 and VEGF are found in COPD and asthma phenotypes. Here, we investigated the DEspR expression on human leukocyte populations of asthmatics, COPD patients and healthy smokers as well as on the human promyelocytic leucaemic cell line HL-60. Methods DEspR expression was measured on undifferentiated, promyelocytic HL-60 cells and after differentiation towards a neutrophilic phenotype using 1.25% DMSO. Expression was also measured after stimulation with 50 μg/mL poly I:C or 100 ng/mL LPS. Whole blood cells of COPD patients (step III, IV), healthy smokers and asthmatics (step III) were stained directly after blood draw or after stimulation with 50 μg/mL poly I:C or 100 ng/mL LPS. HL-60 and whole blood leukocytes were stained with Annexin V, 7AAD, DEspR (rhIgG4, clone 6g8), CD11b, CD14 and CD16a. Results Undifferentiated CD11b-, CD14- CD16a- and differentiated CD11b+, CD14-, CD16a- HL-60 cells did not express DEspR, neither with or without inflammatory stimulation. DespR was not expressed on whole blood leukocytes at baseline level (mean±SD: 0.15±0.26 to 0.91±0.60%) but poly I:C induced DEspR expression on neutrophils (34.10±18.52%), monocytes (29.16±20.00%), lymphocytes (9.67±6.11%) and eosinophils (6.14±4.39%). The distribution of DEspR+ cells upon poly I:C stimulation was not significantly altered among different disease types, however, healthy smokers showed a trend to higher DEspR levels. The median fluorescence intensity was not significantly altered among disease types but among the cell populations. Conclusion First experiments demonstrated that DEspR expression can be induced on leukocytes upon inflammatory stimulation. In contrast to previous results of us, LPS did not induce DEspR expression which might be related to differences in the age and disease severity of investigated patients. Interestingly, poly I:C induced a strong DEspR expression indicating a toll-like receptor 3 related mechanism. The sample size needs to be increased to confirm these first results and to investigate the underlying mechanism in detail.

Endothelin-1 axes in the framework of predictive, preventive and personalised (3P) medicine.

Endothelin-1 (ET-1) is involved in the regulation of a myriad of processes highly relevant for physical and mental well-being; female and male health; in the modulation of senses, pain, stress reactions and drug sensitivity as well as healing processes, amongst others. Shifted ET-1 homeostasis may influence and predict the development and progression of suboptimal health conditions, metabolic impairments with cascading complications, ageing and related pathologies, cardiovascular diseases, neurodegenerative pathologies, aggressive malignancies, modulating, therefore, individual outcomes of both non-communicable and infectious diseases such as COVID-19. This article provides an in-depth analysis of the involvement of ET-1 and related regulatory pathways in physiological and pathophysiological processes and estimates its capacity as a predictor of ageing and related pathologies,a sensor of lifestyle quality and progression of suboptimal health conditions to diseases for their targeted preventionand as a potent target for cost-effective treatments tailored to the person.

Eosinopenia and increased markers of endothelial damage are characteristic of COVID-19 infection at time of hospital admission.

In December 2019, a new virus has been discovered, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), leading to coronavirus disease 2019 (COVID-19). COVID-19 has been defined as an evolving disease with different phases. It starts with a mild or asymptomatic phase in which there is minimal disease. Thereafter, most patients recover, however, in 20% of the cases the infection worsens. It is hypothesized that eosinopenia, endothelial injury and the presence of smooth muscle autoantibodies are associated with the severity of the COVID-19. In a subset of 75 blood samples of patients with a SARS-CoV-2 infection at time of hospitalization and 30 healthy control samples concentrations of eosinophils, VEGF, VCAM, endothelin and smooth muscle autoantibodies were determined with hemocytometry, ELISA and immunofluorescence assays. In the group of patients with COVID-19 eosinophils (IQR = 0.0-0.01*109/L) were significantly decreased (p < .001), whereas markers of endothelial damage VCAM (IQR = 740-1120 ng/mL) and endothelin (IQR = 2.0-3.4 pg/mL) were significantly increased (p < .001) compared to the group of healthy controls (eosinophils IQR = 0.09-0.19*109/L, VCAM IQR = 362-561 ng/mL, endothelin IQR = 0.5-1.0 pg/mL). From the multivariate analysis, it is concluded that at time of hospitalization a combination of eosinopenia and increased markers of endothelial damage VCAM and endothelin are characteristic of COVID-19.

LEVELS OF ENDOTHELIN-1 AND HIGH MOLECULAR WEIGHT KININOGEN IN BLOD OF BREAST CANCER PATIENTS AFTER SARS-COV-2 INFECTION

The aim. To analyze the blood levels of endothelin-1 (ET - 1) and high molecular weight kininogen (HMWK) in patients with breast cancer (BC) previously infected with the new coronavirus. Material and methods. The study group included 20 patients with stage II - IV BC (invasive carcinoma). All patients were receiving chemotherapy at the time of their SA RS-CoV-2 infection. The comparison group included 19 women without breast cancer, who were matched for age. All women of both groups had an RT-PC R confirmed SA RS-Cov-2 infection. Blood levels of ET - 1 and HMWK were measured by ELISA 3-10 weeks after the positive antigen test results. The control group included 10 women of the same age without cancer and without CO VID - 19 symptoms and anti-SA RS-CoV-2 antibodies. Results. The ET - 1 levels in the comparison group were within the reference range, while HMWK levels were significantly higher than those in breast cancer patients. In BC patients with lung metastases, the ET - 1 levels were higher than those in the comparison group patients, while in others (no history of lung metastases, with mild infection course or pneumonia), the ET - 1 levels were similar to those in the comparison and control groups. The HMWK levels in the study and comparison groups were significantly higher than those in controls. Among BC patients, there were women who had significantly higher ET - 1 and HMWK levels compared to the reference levels, and the majority of these patients had lung metastases and previous CO VID - 19 pneumonia. Conclusion. The measurement of HMWK blood levels demonstrated that the plasma contact activation system and the kallikrein-kinin system were active for a long period after the infection both in BC patients and in women without cancer. A high level of ET - 1, the endothelial dysfunction marker, persisted for a long time in some BC patients. Our results were consistent with results of other studies supporting the hypothesis that SA RS-CoV-2 virus infection is a systemic vascular disease with long-term consequences, and its mechanisms require further study.

Molecular Effects of Auto-Antibodies on Angiotensin II Type 1 Receptor Signaling and Cell Proliferation.

The angiotensin II (Ang II) type 1 receptor (AT1R) is involved in the regulation of blood pressure (through vasoconstriction) and water and ion homeostasis (mediated by interaction with the endogenous agonist). AT1R can also be activated by auto-antibodies (AT1R-Abs), which are associated with manifold diseases, such as obliterative vasculopathy, preeclampsia and systemic sclerosis. Knowledge of the molecular mechanisms related to AT1R-Abs binding and associated signaling cascade (dys-)regulation remains fragmentary. The goal of this study was, therefore, to investigate details of the effects of AT1R-Abs on G-protein signaling and subsequent cell proliferation, as well as the putative contribution of the three extracellular receptor loops (ELs) to Abs-AT1R signaling. AT1R-Abs induced nuclear factor of activated T-cells (NFAT) signaling, which reflects Gq/11 and Gi activation. The impact on cell proliferation was tested in different cell systems, as well as activation-triggered receptor internalization. Blockwise alanine substitutions were designed to potentially investigate the role of ELs in AT1R-Abs-mediated effects. First, we demonstrate that Ang II-mediated internalization of AT1R is impeded by binding of AT1R-Abs. Secondly, exclusive AT1R-Abs-induced Gq/11 activation is most significant for NFAT stimulation and mediates cell proliferation. Interestingly, our studies also reveal that ligand-independent, baseline AT1R activation of Gi signaling has, in turn, a negative effect on cell proliferation. Indeed, inhibition of Gi basal activity potentiates proliferation triggered by AT1R-Abs. Finally, although AT1R containing EL1 and EL3 blockwise alanine mutations were not expressed on the human embryonic kidney293T (HEK293T) cell surface, we at least confirmed that parts of EL2 are involved in interactions between AT1R and Abs. This current study thus provides extended insights into the molecular action of AT1R-Abs and associated mechanisms of interrelated pathogenesis.

Endothelial dysfunction and altered endothelial biomarkers in patients with post-COVID-19 syndrome and chronic fatigue syndrome (ME/CFS).

BACKGROUND: Fatigue, exertion intolerance and post-exertional malaise are among the most frequent symptoms of Post-COVID Syndrome (PCS), with a subset of patients fulfilling criteria for Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS). As SARS-CoV-2 infects endothelial cells, causing endotheliitis and damaging the endothelium, we investigated endothelial dysfunction (ED) and endothelial biomarkers in patients with PCS. METHODS: We studied the endothelial function in 30 PCS patients with persistent fatigue and exertion intolerance as well as in 15 age- and sex matched seronegative healthy controls (HCs). 14 patients fulfilled the diagnostic criteria for ME/CFS. The other patients were considered to have PCS. Peripheral endothelial function was assessed by the reactive hyperaemia index (RHI) using peripheral arterial tonometry (PAT) in patients and HCs. In a larger cohort of patients and HCs, including post-COVID reconvalescents (PCHCs), Endothelin-1 (ET-1), Angiopoietin-2 (Ang-2), Endocan (ESM-1), IL-8, Angiotensin-Converting Enzyme (ACE) and ACE2 were analysed as endothelial biomarkers. RESULTS: Five of the 14 post-COVID ME/CFS patients and five of the 16 PCS patients showed ED defined by a diminished RHI (< 1.67), but none of HCs exhibited this finding. A paradoxical positive correlation of RHI with age, blood pressure and BMI was found in PCS but not ME/CFS patients. The ET-1 concentration was significantly elevated in both ME/CFS and PCS patients compared to HCs and PCHCs. The serum Ang-2 concentration was lower in both PCS patients and PCHCs compared to HCs. CONCLUSION: A subset of PCS patients display evidence for ED shown by a diminished RHI and altered endothelial biomarkers. Different associations of the RHI with clinical parameters as well as varying biomarker profiles may suggest distinct pathomechanisms among patient subgroups.

Endothelin-1 is increased in the plasma of patients hospitalised with Covid-19.

Virus induced endothelial dysregulation is a well-recognised feature of severe Covid-19 infection. Endothelin-1 (ET-1) is the most highly expressed peptide in endothelial cells and a potent vasoconstrictor, thus representing a potential therapeutic target. ET-1 plasma levels were measured in a cohort of 194 Covid-19 patients stratified according to the clinical severity of their illness. Hospitalised patients, including those who died and those developing acute myocardial or kidney injury, had significantly elevated ET-1 plasma levels during the acute phase of infection. The results support the hypothesis that endothelin receptor antagonists may provide clinical benefit for certain Covid-19 patients.

Caution, "normal" BMI: health risks associated with potentially masked individual underweight-EPMA Position Paper 2021.

An increasing interest in a healthy lifestyle raises questions about optimal body weight. Evidently, it should be clearly discriminated between the standardised "normal" body weight and individually optimal weight. To this end, the basic principle of personalised medicine "one size does not fit all" has to be applied. Contextually, "normal" but e.g. borderline body mass index might be optimal for one person but apparently suboptimal for another one strongly depending on the individual genetic predisposition, geographic origin, cultural and nutritional habits and relevant lifestyle parameters-all included into comprehensive individual patient profile. Even if only slightly deviant, both overweight and underweight are acknowledged risk factors for a shifted metabolism which, if being not optimised, may strongly contribute to the development and progression of severe pathologies. Development of innovative screening programmes is essential to promote population health by application of health risks assessment, individualised patient profiling and multi-parametric analysis, further used for cost-effective targeted prevention and treatments tailored to the person. The following healthcare areas are considered to be potentially strongly benefiting from the above proposed measures: suboptimal health conditions, sports medicine, stress overload and associated complications, planned pregnancies, periodontal health and dentistry, sleep medicine, eye health and disorders, inflammatory disorders, healing and pain management, metabolic disorders, cardiovascular disease, cancers, psychiatric and neurologic disorders, stroke of known and unknown aetiology, improved individual and population outcomes under pandemic conditions such as COVID-19. In a long-term way, a significantly improved healthcare economy is one of benefits of the proposed paradigm shift from reactive to Predictive, Preventive and Personalised Medicine (PPPM/3PM). A tight collaboration between all stakeholders including scientific community, healthcare givers, patient organisations, policy-makers and educators is essential for the smooth implementation of 3PM concepts in daily practice.

Antibodies against Angiotensin II Type 1 and Endothelin 1 Type A Receptors in Cardiovascular Pathologies.

Angiotensin II receptor type 1 (AT1R) and endothelin-1 receptor type A (ETAR) are G-protein-coupled receptors (GPCRs) expressed on the surface of a great variety of cells: immune cells, vascular smooth cells, endothelial cells, and fibroblasts express ETAR and AT1R, which are activated by endothelin 1 (ET1) and angiotensin II (AngII), respectively. Certain autoantibodies are specific for these receptors and can regulate their function, thus being known as functional autoantibodies. The function of these antibodies is similar to that of natural ligands, and it involves not only vasoconstriction, but also the secretion of proinflammatory cytokines (such as interleukin-6 (IL6), IL8 and TNF-α), collagen production by fibroblasts, and reactive oxygen species (ROS) release by fibroblasts and neutrophils. The role of autoantibodies against AT1R and ETAR (AT1R-AAs and ETAR-AAs, respectively) is well described in the pathogenesis of many medical conditions (e.g., systemic sclerosis (SSc) and SSc-associated pulmonary hypertension, cystic fibrosis, and allograft dysfunction), but their implications in cardiovascular diseases are still unclear. This review summarizes the current evidence regarding the effects of AT1R-AAs and ETAR-AAs in cardiovascular pathologies, highlighting their roles in heart transplantation and mechanical circulatory support, preeclampsia, and acute coronary syndromes.

Pulmonary artery targeted therapy in treatment of COVID-19 related ARDS. Literature review.

INTRODUCTION: The most grievous complication of the COVID-19 is the acute respiratory distress syndrome. A specific, rescue treatment for rapidly deteriorating patients should emerge to improve respiratory function and help patients to survive the most challenging period. Drugs used in targeted therapy of pulmonary arterial hypertension (PAH) appears to be suitable for this task and this article describes their potential for treatment of severe cases of COVID-19. METHODS: The authors reviewed the following databases for randomized controlled trials, reviews and meta-analyses published up to July 2020: Pubmed, Scopus, Google Scholar, Cochrane Database and ClinicalKey. The authors included every study contributory to the assessment of the potential of drugs used in targeted PAH therapy in treatment of COVID-19. RESULTS: Endothelin receptor antagonists, phosphodiesterase 5 inhibitors, riociguat and prostacyclin have proven ani-inflammatory effect and reduce pulmonary artery blood pressure, lung oedema and remodelling. Bosentan shows antiviral properties and sildenafil, as well as epoprostenol, inhibits apoptosis of lung epithelial cells. Among patients with lung lesions the decrease of pulmonary blood pressure can lead to increase of ventilation/perfusion mismatch and decrease of blood oxygenation. CONCLUSIONS: Among all assessed drugs bosentan, sildenafil and epoprostenol appear to be most promising and a combination of these drugs should be considered due to synergism. The targeted PAH therapy in treatment of COVID-19 associated ARDS could be a useful tool saving lives of patients with severe SARS-CoV-2 infection, however, its introduction should be investigated and monitored very carefully as it can lead to transient deterioration of patient condition.

Sustained endothelial, coagulation and inflammatory cytokine activation without macrovascular dysfunction at 3 months after COVID-19: A reflection on SARS-CoV-2 induced thrombo-inflammation

Background: Endothelial damage caused by COVID-19 may imperil the cardiovascular health of millions. More than a year since WHO declared the COVID-19 pandemic, information on the lasting effects of this infection on the cardiovascular system beyond the acute phase is still lacking. Purpose: To study macrovascular endothelial dysfunction and activation, coagulation and inflammation, 3 months after resolution of acute COVID- 19 symptoms. Methods: A cross-sectional observational cohort study was conducted including 203 patients with PCR confirmed COVID-19 disease, 6-20 weeks after acute COVID-19. The primary endpoint was macrovascular endothelial function, assessed by the carotid artery reactivity (CAR) test. The CAR measures the carotid artery diameter in response to hand in icewater immersion. A historic cohort of 313 subjects served as controls. Propensity score matching was used to correct for baseline differences. Plasma endothelin-1 (ET-1), interleukin (IL)-1ra, IL-6, IL-18 were measured by ELISA. ET-1 levels were also measured in a partially overlapping COVID-19 cohort of which plasma samples were available during the acute phase. Coagulation enzyme:inhibitor complexes for thrombin:antithrombin (TAT), factor (F) IXa:AT, FVIIa:AT, FXIa:AT, FXIa:alpha 1 antitrypsin (a1AT), FXIa:C1 esterase inhibitor (C1inh), kallikrein(PKa):C1inh and von Willebrand Factor:antigen (vWF:Ag), were assessed by in house developed ELISA. Results: After propensity score matching, the prevalence of macrovascular dysfunction did not differ between the COVID-19 (22.5%) versus the historical control cohort (18.6%, RD -3.92%, 95%-CI -15 to 7.19, p=0.49). Plasma concentrations of markers for endothelial activation were elevated (>1 SD above normal);ET-1 (64.9%), and vWF:Ag (80.8%). In controls, ET- 1 levels were significantly lower as compared to COVID-19 patients during the acute phase and after 3 months. ET-1 levels were significantly higher 3 months after COVID-19 as compared to the acute phase. Cytokines were high in a majority of patients: IL-18 (73.9%), IL-6 (51.2%), and IL- 1ra (48.9%). TAT and FIXa:AT, reflecting a prothrombotic state, were high in 48.3% and 29.6% of the patients, respectively. FVIIa:AT, as marker of the extrinsic pathway, was elevated (35%). Markers of contact activation were also increased: PKa:C1inh (16.3%), FXIa:AT (16.3%), FXIa:a1AT (20.7%), and FXIa:C1inh (17.7%) (picture 1). Conclusions: At 3 months after acute COVID-19 there was no indication of macrovascular dysfunction as compared to matched historic controls;there was evidence, however, of sustained thrombo-inflammation, indicated by high circulating concentrations of ET-1, vWF:Ag, proinflammatory cytokines, and markers of coagulation (picture 2). Elevated IL-18 levels could potentially induce arterial inflammation and subsequent atherogenesis. Our data highlight the importance of further studies on SARS-CoV-2 related thrombo-inflammation, as well as longer follow-ups in recovered patients. (Figure Presented).